Questions
1. Does enzymatic debridement using the agent collagenase remove necrotic debris from the wound bed and promote wound healing in pressure ulcers, leg ulcers, or burn wounds?
2. Does enzymatic debridement using the agent papain-urea remove necrotic debris from the wound bed and promote wound healing in pressure ulcers, leg ulcers, or burn wounds?
Introduction
Debridement is defined as removal of foreign material and devitalized or contaminated tissue from the wound bed until surrounding healthy tissue is exposed.1 Multiple techniques are used to debride wounds; the most common techniques are surgical, conservative sharp, mechanical, high-pressure fluid irrigation, ultrasonic mist, autolysis, enzymatic, larval therapy, and autolysis.2,3 Enzymatic debridement is the application of exogenous enzymes to the wound bed in order to degrade necrotic tissue without harming viable, granulation tissue.
Debridement is considered a necessary component of wound bed preparation, especially in chronic, nonhealing, or indolent wounds considered to be stalled in the inflammatory phase of wound healing.3 Limited evidence exists that directly links debridement to wound healing.4,5 In addition, expert opinion and clinical experience overwhelmingly support its necessity when the wound bed contains necrotic tissue in the form of yellow slough or black eschar. Existing research provides a rational basis for debridement as a component of wound bed preparation in order to (1) reduce the inflammatory cytokines, fibronectin, and metalloproteinases produced when a wound is chronically inflamed owing to the presence of necrotic tissue; (2) promote DNA synthesis and growth of keratinocytes that are inhibited by production of these inflammatory products; and (3) reduce bacterial bioburden associated with necrotic tissue in the wound bed.6-10
Debridement has been incorporated into a conceptual framework focusing on Wound Bed Preparation. This framework was originally described and subsequently refined by Schultz and colleagues.11 It is based on a synthesis of research and clinical experience on the management of indolent or nonhealing (chronic) wounds. Wound Bed Preparation focuses on 4 factors that must be addressed when formulating a treatment plan for a chronic wound, collectively referred to using the acronym TIME, where "T" indicates nonviable or deficient tissue, "I" indicates infection or inflammation, "M" indicates moisture imbalance, and "E" indicates a nonadvancing or undermined wound edge.
While widespread agreement exists concerning the necessity of debridement in wounds with grossly visible necrotic tissue, less agreement exists concerning the optimal technique for removing slough or eschar from the wound.3 Selecting the optimal technique for debriding a specific wound is influenced by multiple factors, including the type and volume of necrotic tissue, the presence of underlying infection or bacterial bioburden, wound size, pain associated with the technique, presence of comorbid conditions including sepsis, vascularity of the wound and adjacent tissue, patient preference, and cost. It may also be impacted by access to providers, particularly in home care and long-term care.
Enzymatic debridement is frequently used either alone or in combination with other techniques such as surgical debridement, to remove necrotic tissue and promote wound healing.3,12 It can be used in patients with infected or contaminated wounds, patients on anticoagulant therapy when surgical debridement is not feasible, and on either yellow slough or black eschar. Enzymatic debriding agents are typically applied daily or twice daily depending on the agent. They are applied directly to the wound bed and may produce a transient stinging sensation that some patients find distressing. Some patients may be hypersensitive to the enzyme or another component within its delivery vehicle. Clinicians are advised to cleanse the wound and to cross-hatch black eschar before applying an enzymatic debriding agent. The purpose of this Evidence-Based Report Card is to identify and review existing evidence concerning the effectiveness of 2 enzymes, collagenase and papain-urea, for debriding pressure ulcers, leg ulcers, or diabetic foot ulcers. Based on the existing research, the primary outcome we selected was time required to remove visible necrotic material from the wound bed. Time to wound healing, the preferred outcome, was reported when available, but it was not measured in the majority of studies identified.
Methods
A systematic review of electronic databases MEDLINE and CINAHL (from January 1960 to February 2008) was undertaken using the following key words: (1) debridement, (2) enzymatic debridement, (3) collagenases, (4) papain, (5) urea, and (6) papain-urea. Boolean features of these databases were used to combine these terms with the following key words: (1) wound healing, (2) pressure ulcer, (3) varicose ulcer, (4) leg ulcer, and (5) diabetic foot. All prospective and retrospective studies that compared enzymatic debridement using collagenase or papain-urea (with and without chlorophyllin) on pressure ulcers, leg ulcers, or burn wounds were included in the review. Studies focusing on children and adults were included; studies reporting in vivo or in vitro model data were excluded. Prospective and retrospective case studies and multiple case series were excluded. Studies published in English and those with an English language abstract were included. The Cochrane Database for Systematic Reviews was searched using the key term debridement. The ancestry of review articles and research reports were searched for additional studies. Finally, the Web-based engine, Google Scholar, was searched using the key terms: (1) debridement, (2) enzymatic debridement, (3) collagenase, and (4) papain-urea.
Question 1: Does enzymatic debridement using the agent collagenase remove necrotic debris from the wound bed and promote wound healing in pressure ulcers, leg ulcers, or burn wounds?
Nine studies were identified that compared enzymatic debridement with a petrolatum-based ointment, placebo ointment, autolytic debridement, surgical excision, silver sulfadiazine, or alternative enzymatic agents (papain-urea and trypsin/chymotrypsin)13-22 (Table 1). Five randomized clinical trials were identified that compared collagenase derived from a bacterial source to a placebo comprising a heat-inactivated collagenase ointment or a petrolatum-based ointment never charged with the enzymatic agent.13-17
Collagenase Versus Placebo
Boxer and coinvestigators13 compared two 0.5% collagenase preparations to a heat-inactivated ointment in 47 subjects with either pressure ulcers or leg ulcers. Collagenase was administered in a petrolatum-based ointment or as a hydrophilic gum that required hydration to achieve the desired concentration of 0.5%. The gum preparation also contained neomycin; the authors did not comment on what actions were taken to maintain the blind when the hydrophilic gum was administered. The majority of their study population had more than 1 ulcer, and analysis of results was based on 62 wounds. The volume of necrotic tissue at baseline was evaluated using an ordinal scale, where 1 indicated minimal debris in the wound bed with subclinical necrosis, 2 indicated a thin layer of necrotic tissue, 3 indicated a thick layer of necrotic tissue, and 4 indicated marked, heaped-up necrotic materials. No distinction between eschar and slough was indicated in the research report. The efficiency of debridement was indicated via an estimate of the percentage of reduction (varying from 0% to 100%) in wound area covered by necrotic tissue and changes in the thickness of necrotic tissue. The efficiency of debridement in level 1 wounds was evaluated based on the percentage of granulation tissue observed in the wound bed. Wounds were cleansed with sterile water and water-soaked gauze, and the ointment or gum preparation was applied directly to the wound. Wounds were treated over variable time periods until complete debridement was obtained varying from 1 week to 14 weeks. Significantly more wounds (58/62, 94%) managed by the collagenase preparations achieved complete debridement as compared to 1 of 8 lesions (13%) in the wounds treated by the placebo ointment (P < .01). No significant difference in the efficiency of debridement was noted when the collagenase ointment and collagenase gum with neomycin-treated wounds were compared. The researchers reported that no hypersensitivity reactions occurred. No clinically relevant adverse side effects occurred; some subjects treated with collagenase over a period of multiple weeks developed mild erythema adjacent to the wound that subsided when application of the enzymatic agent was discontinued. Wound healing outcomes were not reported.
Lee and Ambrus14 compared collagenase to an inactivated ointment in 11 subjects with 28 pressure ulcers. Pressure ulcers were randomized to treatment with 250 N-units/g of collagenase per gram in a petrolatum ointment or a heat-inactivated ointment. The wound was cleansed and the ointment applied twice daily; treatment was continued for 4 weeks. The primary outcome of interest to this review, time to removal of necrotic tissue, was not reported as a separate outcome. Instead, it was ranked as one part of a global improvement scale that also included inflammation and purulent exudate in the wound bed. A 4-point scale was reported, where 0 indicated no necrotic or purulent materials, 1 indicated mild inflammation and necrotic materials, 2 indicated moderate inflammation and necrotic material, and 3 indicated severe inflammation and necrosis. Two diameters of the pressure ulcer were completed and a volume mold used for dental impressions was made to measure wound volume. Fourteen of 17 (82%) wounds treated with the collagenase ointment were evaluated as improved, whereas no wound treated with the placebo ointment was considered improved. Analysis of differences in wound diameter and wound volume was not reported. However, the researchers did comment that some wounds increased in volume following treatment but were ranked as improved. The increase in wound volume was attributed to successful removal of necrotic and inflammatory debris from the wound.
Varma and associates15 compared a petrolatum-based ointment containing collagenase 250 N-units/g with a heat-inactivated placebo ointment in a double-blind, placebo-controlled, randomized clinical trial. Twenty subjects were enrolled in the trial and 1 wound was treated in each subject; this ulcer was selected randomly in subjects who presented with multiple pressure ulcers. Ten ulcers were treated with the collagenase ointment and 10 were treated with the placebo ointment; participants had either pressure ulcers or leg ulcers. Subjects with eschar underwent cross-hatching using a no. 10 blade prior to treatment. After cleansing, all ulcers were also dusted with a powder containing polymyxin B, bacitracin, and neomycin. Treatment continued over a 2-week period. Similar to Lee and Ambrus,14 the efficiency of debridement was evaluated using a 4-point ordinal scale that ranked the degree of necrotic material in wound bed, purulent discharge, and signs of inflammation. The researchers reported that wound area was measured, but the technique used was not described. When compared with placebo, wounds treated with the collagenase showed a significant reduction in the ordinal scale ranking necrosis and inflammation (P < .01). No significant difference in wound size was found (P < .07) after 2 weeks of treatment. No adverse reactions were observed with the exception of erythema in 1 subject when the ointment was applied to the periwound skin as well as the wound bed. This response, which subsided within 24 hours after application, was limited to the wound bed.
Palmieri and Magri16 reported a placebo-controlled, double-blind randomized clinical trial of 30 subjects with leg ulcers. Subjects were randomly assigned to treatment with a collagenase-based ointment or petrolatum ointment applied once daily to the wound over a 2-week period. They also combined elements of wound healing with magnitude of necrotic tissue removal, using a 5-point Likert scale that evaluated debridement, reepithelialization, inflammation, granulation, and a global efficacy score. After 6 days, wounds managed by collagenase were ranked as having significantly less necrotic materials than those managed with the placebo ointment. After 14 days, subjects treated by the collagenase ointment achieved statistically significant differences on all variables ranked in the 5-point scale when compared to those managed by the petrolatum ointment. Five subjects in each group experienced adverse reactions including a burning sensation experienced after application of the ointment and erythema of the wound bed. All events were characterized as mild and none led to study withdrawal.
Fu and colleagues17 compared an ointment-based collagenase preparation with a petrolatum-based ointment in a double-blind, placebo-controlled, randomized clinical trial. This study was published in the Chinese Medical Sciences Journal; it contains an English language abstract only. Sixty subjects with burn wounds were enrolled; 33 were randomized to treatment with the collagenase ointment and 29 were randomized to treatment with the petrolatum ointment. The ointment was applied to the wound daily and covered with saline-soaked gauze. Efficacy was based on changes in 5 variables: debridement, granulation tissue formation, reepithelialization, inflammatory state, and wound size. The wound area was measured by tracing the wound edges on a clear plastic overlay, and a global efficacy score was calculated based on assessment of debridement effect, reepithelialization, and granulation tissue. Wounds treated with both collagenase and petrolatum ointment achieved reductions in necrotic tissue burden over the 2-week data collection period, but a greater number of wounds managed by the collagenase ointment had a reduction of 50% or more than did those managed by the petrolatum ointment alone. Wound area, reepithelialization, granulation tissue formation, and global efficacy scores were better in the collagenase group as compared to the control group when wounds were assessed at 4, 7, 11, and 14 days. Twenty-two of 33 subjects (67%) treated by the collagenase ointment achieved wound closure by day 14; the number of wounds in the control group that closed by day 14 was not reported in the abstract. A global tolerability rating revealed that 100% of subjects managed by petrolatum ointment and 97% of those managed by the collagenase ointment had a "very good tolerance" of treatment.
Collagenase Versus Other Active Treatments
A single study was identified that compared a bacterial-derived collagenase ointment with silver sulfadiazine for burn wounds. Soroff and Sasvary18 reported 15 subjects with partial-thickness burn wounds covering less than 25% of their body surface area. Participants were randomized to treatment with collagenase ointment and a polymyxin B sulfate/bacitracin spray or a silver sulfadiazine cream applied twice daily. Wounds were cleansed with saline; the collagenase ointment or silver sulfadiazine cream was applied directly to the wound using a tongue depressor or with a sterile, gloved hand. They reported both outcomes of interest separately: the number of days until the wound bed was "clean" (defined as free from injured dermis) and the number of days until the wound healed (defined as appearance of a new layer of epithelium). The median time to a clean wound bed and the median time to wound healing were faster among subjects randomized to the collagenase ointment group. All but 1 patient in the collagenase group achieved wound healing within 15 days. Adverse events included 3 subjects who experienced burn at the site treated with collagenase; this led 1 subject to discontinue participation in the study.
One study was identified that compared enzymatic to autolytic debridement, using a polyacrylate dressing designed to support the autolytic process. Konig and coinvestigators19 evaluated 42 adult subjects with venous ulcers. Fifteen subjects were managed by autolytic debridement and 27 were managed by a collagenase ointment. All subjects underwent a 7-day washout period in which they used no topical treatments other than a dressing used to cover and protect the leg ulcer. Subjects managed by autolysis applied a polyacrylate dressing that was activated by wetting with Ringer's solution before dressing the wound. The dressing was changed once daily. Subjects randomized to treatment with the collagenase were taught to apply the ointment to the wound bed once daily and cover the wound with dry gauze. They also changed the dressing once daily. Subjects in both groups were taught to use short-stretch compression bandages during waking hours. The original study design specified a data collection period of 14 days, but this was extended to 21 days owing to considerable variability and lack of meaningful changes during the first 2 weeks of treatment. During the initial 14 days, subjects managed by autolytic debridement experienced a mean 20% reduction in necrotic tissue, whereas those managed by collagenase experienced a mean reduction of 10%. During the following week, subjects managed by autolytic debridement experienced an additional mean reduction in necrotic tissue of 11%, whereas those managed by collagenase had a mean increase in necrotic tissue burden of 11%. No statistically significant differences were found when results were compared between the groups.
Two studies were identified that compared collagenase to other enzymatic debriding agents. Alvarez and coworkers20 compared a petrolatum ointment containing 250 N-units of collagenase/g with a hydrophilic ointment containing the enzymatic debriding agent papain (8.3 / 105 USP activity/g) and urea (100 mg/g) in a randomized clinical trial involving 26 patients with pressure ulcers. Neither subjects nor investigators were blinded. Wounds were cleansed with sterile normal saline before application of the enzymatic debriding agent, and black eschar was crosshatched using a no. 10 blade prior to treatment. The debriding agent was applied directly to the wound bed once daily, and the wound was dressed with moist gauze and covered by dry gauze sufficient to ensure a moist wound-healing environment. If the wound became soiled, dressings were changed and 1 additional application per day was permitted. Patients were maintained on pressure redistribution surfaces when indicated; use or type of surface was not standardized for study subjects. Wounds were evaluated daily for 1 week and then twice weekly for the following 3 weeks of data collection.
Necrotic tissue was characterized as adherent yellow/gray or white slough, soft adherent black eschar, or adherent hard black eschar. The line of demarcation between nonviable and viable tissue was estimated and a global evaluation of the wound was completed based on evaluation of wound edges, odor, pain, exudate, edema, erythema, granulation tissue, reepithelialization, and periwound skin irritation. Wound size was determined based on computer planimetry of surface tracings. The primary endpoint of the study was removal of necrotic tissue; wound healing was evaluated via the global wound evaluation described above and presence of granulation tissue. The papain-urea ointment dissolved necrotic tissue more rapidly than did wounds treated by the collagenase ointment, resulting in significantly greater presence of granulation tissue in the wound bed. However, the rate of reepithelialization and wound closure did not differ between subjects treated with collagenase versus papain-urea-based ointments.
Glyantsev and associates21 reported in vitro, in vivo, and clinical studies comparing a collagenase-based ointment to a trypsin/chymotrypsin debriding agent commercially available in Russia. Unlike the previous studies, the collagenase evaluated by Glyantsev's group was derived from the liver of the king crab, rather than a bacterial source. Twenty-one subjects with chronic venous leg ulcers were assigned to treatment either with a 0.5% collagenase ointment or a 0.5% trypsin/chymotrypsin ointment. Ulcer sizes varied from 5.5 to 40.0 mm2. The ulcers had been present for an average of 7.5 months in the collagenase group and 9 months in the comparison group; all ulcers had signs of infection and yellow slough. Treatment comprised twice daily application of application of the enzymatic debriding agent (collagenase vs trypsin/chymotrypsin) as part of a wet-to-moist dressing technique. The periwound skin was dressed with povidone-iodine foam pads and "moderate compression bandages." Subjects managed by collagenase became free from visible slough in the wound bed significantly sooner than subjects managed by the trypsin/chymotrypsin debriding agent (5.6 +/- 0.3 days vs 10.3 +/- 0.9 days, P < .01).
Finally, a single study was identified that compared debridement using a bacterial-derived collagenase ointment to surgical excision. Ozcan and colleagues22 compared 78 children managed by collagenase to a group of 41 subjects managed by surgical excision. Groups were not randomized; treatment decisions were based on clinical judgments. One hundred nineteen children with noninfected partial-thickness burn wounds participated in the study. In addition to these groups, the authors reported 29 patients who were begun on debridement using collagenase ointment, but treatment was discontinued because they developed a wound infection (n = 17) or their physician decided that wound grafting was indicated (n = 12). The time required for complete removal of necrotic tissue using these 3 methods (collagenase alone, collagenase plus surgical management, or surgical management only) was not significantly different. Patients managed with collagenase alone were less likely to require blood transfusion than those managed with collagenase and surgical intervention or those managed by surgical means alone. Patients initially managed with collagenase were less likely to require additional surgical excision than those managed exclusively by surgical means. Patients managed with collagenase also had a shorter length of stay in hospital than those managed by surgery alone or collagenase followed by surgical intervention.
The 5 studies that compared collagenase to a placebo ointment consistently found that collagenase provided more rapid and effective removal of necrotic tissue than the placebo.13-17 Collagenase removed slough more rapidly than a trypsin/chymotrypsin debriding ointment commercially available in Russia.20 In contrast, collagenase removed necrotic tissue more slowly than a papain-urea-based ointment in a randomized clinical trial of elder adults with pressure ulcers, but the rate of wound closure between the 2 techniques did not differ,19 suggesting equivocal efficacy in promotion of wound healing. Equivocal results were found when collagenase was compared to autolytic debridement in a study of elder adults with leg ulcers, but this study's power in detecting differences was limited by variability in reported data and short duration of data collection. Results of a comparison cohort study suggest that debridement with collagenase is equivocal to surgical excision alone in children with partial-thickness burns and that treatment with collagenase may reduce the need for excision if the techniques are combined. However, the lack of randomization to treatment group severely limits the ability to draw firm conclusions.
Only one study reported wound healing outcomes and time to complete debridement.18 It revealed that treatment of partial-thickness burns covering less than 25% of total body surface area healed more quickly using collagenase as compared to silver sulfadiazine.
Question 2: Does wound bed debridement using the enzymatic agent papain-urea remove debris from the wound bed and increase the rate of wound healing in pressure ulcers and leg ulcers?
A single randomized clinical trial was located that evaluated a papain-urea-based ointment. As described previously, Alvarez and coworkers20 compared a hydrophilic ointment containing papain (8.3 / 105 USP activity/g) and urea (100 mg/g) to a white petrolatum ointment containing 250 N-units of collagenase/g. The study setting was 3 long-term care facilities; 26 patients with pressure ulcers were enrolled. Study procedures were described previously. When compared to pressure ulcers managed by the collagenase ointment, those managed by papain-urea ointment achieved significantly greater reduction in visible necrotic tissue during weeks 2, 3, and 4 of treatment. In addition, wounds managed by papain-urea had greater visible granulation tissue during this period. Nevertheless, these results must be carefully weighed against the finding that subjects in both groups experienced similar contractions in wound size, suggesting equivocal outcomes in healing rates.
KEY POINTS
[check mark] Collagenase ointment is more effective than placebo (inactivated ointment or petrolatum ointment) for debridement of necrotic tissue from pressure ulcers, leg ulcers, and partial-thickness burn wounds. (Level of Evidence: 1)
[check mark] There is insufficient evidence to determine whether collagenase ointment removes necrotic tissue from leg ulcers more or less rapidly than autolytic debridement enhanced by a polyacrylate dressing. (Level of Evidence: NA)
[check mark] Limited evidence suggests that a papain-urea-based ointment removes necrotic material from pressure ulcers more rapidly than collagenase ointment, but progress toward wound healing appears to be equivocal. (Level of Evidence: 1)
[check mark] Limited evidence suggests that treatment of partial-thickness burn wounds in children with collagenase ointment may require an equivocal time to treatment with surgical excision and that combination treatment may reduce the need for surgical excision. (Level of Evidence: 2)
CLINICAL IMPLICATIONS
[check mark] Enzymatic debriding agents are an effective alternative for removing necrotic material from pressure ulcers, leg ulcers, and burn wounds. These agents are indicated for use on both slough and eschar. Enzymatic agents may be used as the primary technique for debridement, especially when alternative methods are not an option. Many clinicians combine enzymatic agents with other methods, and clinical experience suggests that combination therapy is effective in removing adherent necrotic tissue in selected wounds. Combined therapy often involves initial surgical debridement, followed by serial debridement with an enzymatic agent and conservative sharp wound debridement at each dressing change. Autolytic debridement may be enhanced by the ointment vehicle and the cover dressing selection.
[check mark]The wound should be cleansed prior to application with normal saline or a pH neutral cleanser. Care should be taken to avoid any products containing metal, including silver dressings or products, because they diminish the biologic activity of collagenase and papain-urea.3 The product is applied directly to the wound, daily or twice daily. Enzymatic agents should not be combined. One of the available products suggest the use of antibiotic powder if the wound bed shows signs of excessive bioburden or infection; however, this is commonly done with both products and there is no known contraindication. Intact eschar should be cross-hatched with a no. 10 surgical blade to enable penetration of the enzyme. Alternatively, the enzyme may be applied to the periphery of the wound to facilitate separation. Care should be taken to protect the periwound skin. Papain-urea is also available in a spray delivery system, which was preferred for ease of use when compared with the ointment formulation in one study.23
[check mark] Gauze was the recommended dressing choice since early studies on both collagenase and papain-urea were conducted before the use of moisture-retentive dressings. Experience has shown that clinicians commonly select a dressing based on the wound characteristics. A variety of dressings, such as gauze, thin foams, and transparent film dressings, can be safely used and may actually potentiate debridement, although the exact effect on efficacy is unknown. Factors such as presence of infection, wound drainage, wound location, wound size and depth, cost, and the need for daily application of the enzyme should be considered when selecting a dressing for use with enzymes.
[check mark] Clinicians may find that the TIME conceptual framework for wound bed preparation provides a clinically useful framework for guiding clinical decisions about debridement.11
References